Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][OH:7].[Si:13](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CN=C1>CN(C=O)C>[Si:13]([O:7][CH2:6][C:5]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc(CO)cc(OC)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.9 %

Procedure:
A mixture of 3,5-dimethoxybenzyl alcohol (4.0 g), tert-butyl-diphenylsilyl chloride (6.54 g) and imidazole (3.28 g) in DMF (60 mL) was stirred at room temperature for 24 h. DMF was evaporated and the residue was purified by column chromatography (silica gel; eluent: hexane to hexane/EtOAc 20%) to yield 8.5 g of 3,5-dimethoxybenzyl tert-butyldiphenylsilyl ether. ESMS: m/z 407 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[NH2:31]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14]([NH:31][C:30]3[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:28]([O:27][CH3:26])[CH:29]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: COc1ccc(N)cc1OC
Solvent: CC(=O)O
Solvent: O
Product: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccc(OC)c(OC)c3)nc21
Temperature: 160 °C

Procedure:
A mixture of 0.150 g (0.38 mmol) of 6-(2,6-dichlorophenyl)-8-ethyl-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 68 and 0.500 g (3.30 mmol) of 3,4-dimethoxyaniline was heated in a 160° C. oil bath for 5 minutes. The dark blue solution was cooled and dissolved in 2 mL of warm glacial acetic acid. This solution was diluted to 10 mL volume with water to precipitate a solid. The solid was filtered, washed well with water, and dried; wt 0.200 g. Purification was effected by filtration of an ethyl acetate (25 mL) solution through a layer of silica gel and washing the silica gel with ethyl acetate. The filtrate was concentrated to 3 mL volume. The crystals that separated on inducement were filtered and washed with 1 mL of ethyl acetate and then 1 mL of ether; wt 0.116 g; mp 221°-223° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[Li]CCCC.[CH2:15]1[O:25][C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16]1>C1COCC1>[OH:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:21]1([OH:24])[CH2:22][CH2:23][C:18]2([O:25][CH2:15][CH2:16][O:17]2)[CH2:19][CH2:20]1
Reactant: OCc1ccccc1Br
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCc1ccccc1C1(O)CCC2(CC1)OCCO2
Temperature: -4 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromobenzyl alcohol (3.0 g, 16 mmol) in THF (40 mL) cooled at −78° C. was added a 2.5 M solution of n-BuLi in hexanes (14.1 mL). The mixture was stirred at −4° C. for 1 hour and cooled back to −78° C. To it was added a solution of 1,4-cyclohexanedione mono-ethylene ketal (2.5 g, 16 mmol) in TIE (10 mL) over 15 minutes. Stirring was continued at −78° C. for 30 minutes and at −4° C. for 1 hour. The reaction was quenched by addition of a solution of NH4Cl in water. The resulting solution was extracted with EtOAc three times. The combined extract was washed with brine, dried over MgSO4 and concentrated. Purification on silica gel eluting with 5% MeOH/CH2Cl2 provided the title compound. MS calculated (M+H)+ 265, found 287 (M+Na)+.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[O-:2].[NH4+:6].[S:7](=O)([OH:9])[O-:8].[NH4+].S([O-])([O-])=O>>[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[NH4+:6].[NH4+:6].[S:7](=[O:9])=[O:8]
Reactant: O=S([O-])O
Reactant: O=S(=O)([O-])O
Agent: O=S([O-])[O-]
Agent: [NH4+]
Product: O=S(=O)([O-])[O-]
Product: O=S=O

Procedure:
reacting at least a portion of the solution obtained in step (a) with ammonium bisulfate, so as to decompose the ammonium bisulfite and sulfite and to obtain ammonium sulfate in aqueous solution and gaseous sulfur dioxide,
Reaction SMILES: [OH-].[Na+].C1(C[O:10][C:11]([C:13]2([NH:19][C:20]([C:22]3[S:23][C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[CH:26]=3)=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])C=CC=CC=1.CCOCC>O1CCCC1>[S:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[CH:26]=[C:22]1[C:20]([NH:19][C:13]1([C:11]([OH:12])=[O:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:21]
Reactant: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)c1cc2ccccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(NC1(C(=O)O)CCCCC1)c1cc2ccccc2s1
Yield: 83.8 %

Procedure:
42 ml of 2N sodium hydroxide aqueous solution was added to a solution of 10 g (24 mmol) of 1-[(2-benzothienylcarbonyl)amino]cyclohexanecarboxylic acid phenylmethyl ester in 20 ml of tetrahydrofuran, and the mixture was refluxed under heating for 3 days. After ether was added to the reaction solution to wash it, the aqueous layer was neutralized by concentrated hydrochloric acid, and the precipitated crystal was collected by filtration. The obtained crystal was dried under reduced pressure to give 6.1 g (80%) of the title compound.
Reaction SMILES: [CH2:1]([CH:8]([C:13](O)(O)[C:14]([F:17])([F:16])[F:15])[C:9]([O:11]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([N:22]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[S:23]([C:26]1[CH:27]=[N:28][C:29]([NH:32][NH2:33])=[CH:30][CH:31]=1)(=[O:25])=[O:24])[CH3:21]>CO.C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([C:8]1[C:9](=[O:11])[N:32]([C:29]2[N:28]=[CH:27][C:26]([S:23]([N:22]([CH2:20][CH3:21])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)(=[O:25])=[O:24])=[CH:31][CH:30]=2)[NH:33][C:13]=1[C:14]([F:17])([F:16])[F:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(c1ccccc1)S(=O)(=O)c1ccc(NN)nc1
Reactant: COC(=O)C(Cc1ccccc1)C(O)(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCN(c1ccccc1)S(=O)(=O)c1ccc(-n2[nH]c(C(F)(F)F)c(Cc3ccccc3)c2=O)nc1
Temperature: 90 °C
Yield: 12.4 %

Procedure:
A mixture of 1 g (3.59 mmol) of methyl 2-benzyl-4,4,4-trifluoro-3,3-dihydroxybutanoate, 1.05 g (3.59 mmol) of N-ethyl-6-hydrazino-N-phenylpyridine-3-sulfonamide and 1 g of 4 Å molecular sieves in 8 mL of MeOH is heated for 12 hours at 90° C. At room temperature, the reaction medium is taken up in 30 mL of toluene, and refluxed for 12 hours in Dean-Stark apparatus. The reaction medium is then filtered and concentrated under reduced pressure, and the residue obtained is then taken up in 50 mL of DCM, washed with 1N HCl solution (2×50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The solid thus obtained is recrystallized from EtOH. 224 mg of 6-(4-benzyl-5-oxo-3-trifluoromethyl-2,5-dihydro-1H-pyrazol-1-yl)-N-ethyl-N-phenylpyridine-3-sulfonamide are obtained in the form of white crystals.
Reaction SMILES: [CH:1]1([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11](Br)[CH:12]=[CH2:13].CC(C)([O-])C.[K+].Cl>CN(C)C=O.O>[CH2:13]([C:1]1([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: COC(=O)C1CCCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC1(C(=O)OC)CCCCC1
Temperature: 50 °C
Reaction time: 64 h
Yield: 18.7 %

Procedure:
To a solution of methyl cyclohexylcarboxylate (1.42 g) and allyl bromide (3.02 g) in N,N-dimethylformamide (20 mL) was added potassium tert-butoxide (1.68 g, 15.0 mmol) under ice cooling. The solution was stirred at room temperature for 16 hours, at 50° C. for 8 hours and further at room temperature for 64 hours. Water and 3N hydrochloric acid were then added to the solution, and it was extracted with diethyl ether. The extract was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate=97:3) to give the title compound (340 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=1.[C:14]1(N)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C.Cl>[Cl:1][C:2]1[C:7]([C:8]2[NH:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:9]=2)=[CH:6][CH:5]=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=1
Reactant: Nc1ccccc1N
Reactant: CC(C)(C)c1ccc(C#N)c(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2nc3ccccc3[nH]2)c(Cl)n1
Temperature: 220 °C
Reaction time: 0.5 h

Procedure:
A mixture, homogenised in a mortar, of 19.5 g (100 mmol) of 2-chloro-3-cyano-6-tert-butylpyridine (S28), 36.2 g (200 mmol) of o-phenylenediamine and 38.0 g (200 mmol) of p-toluenesulfonic acid monohydrate is heated at 220° C. (oil-bath temperature) for 3 h. After cooling, the black, glassy sinter cake is taken up in a mixture of 100 ml of ethanol and 100 ml of 1N hydrochloric acid with vigorous stirring. After stirring for 30 min., the grey-green solid is filtered off with suction, washed three times with 50 ml of water each time and dried in vacuo. The solid is taken up in 200 ml of ethyl acetate, chromatographed on silica gel (ethyl acetate/heptane 1:1, Rf about 0.7) in order to remove 2-tert-butyl-6,11-dihydrobenzo[b]pyrido[2,3-e]-1,4-diazepin-5-one and brown by-products. The crude product obtained in this way is dissolved in ethyl acetate at the boiling temperature, and four times the amount of cyclohexane is added dropwise. After stirring at room temperature for 18 h, the crystals formed are filtered off with suction, washed with n-heptane and dried in vacuo. Yield: 7.5 g (26 mmol), 26%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[N:26][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:28]4[CH:29]=[N:24][CH:25]=[N:26][CH:27]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: OB(O)c1cncnc1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4cncnc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and pyrimidine-5-boronic acid following a procedure analogous to that described in Example 28. LC (method 7): tR=1.38 min; Mass spectrum (ESI+): m/z=383 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH:9]([F:11])[F:10])[C:5]([F:13])=[C:4]([Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:3]=1.[CH3:21][C:22]([S@:25]([NH2:27])=[O:26])([CH3:24])[CH3:23]>C1COCC1.C(O[Ti](OCC)(OCC)OCC)C>[Br:1][C:2]1[N:7]=[C:6](/[C:8](=[N:27]\[S@@:25]([C:22]([CH3:24])([CH3:23])[CH3:21])=[O:26])/[CH:9]([F:11])[F:10])[C:5]([F:13])=[C:4]([Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:3]=1
Reactant: CC[Si](CC)(CC)c1cc(Br)nc(C(=O)C(F)F)c1F
Reactant: CC(C)(C)[S@](N)=O
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc(Br)nc(/C(=N\[S@](=O)C(C)(C)C)C(F)F)c1F
Temperature: 80 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
A mixture of 1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2,2-difluoroethanone (0.666 g, 1.808 mmol), (R)-2-methylpropane-2-sulfinamide (0.219 g, 1.808 mmol) and tetraethoxytitanium (0.758 ml, 3.62 mmol) in THF (4.52 ml) in a sealed microwave vial was stirred at 80° C. for 3 h. After cooling to RT, the reaction mixture was poured into an ice-cold saturated NaCl solution, stirred for 10 min, and the precipitate was filtered through a pad of celite and washed with EtOAc. The aqueous layer was back extracted with EtOAc (2×) and the combined EtOAc layers were dried (MgSO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provide (R,E)-N-(1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide (0.481 g, 1.020 mmol, 56.4% yield) as dark-brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:9][C:10]=2[C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1.[C:22]([O-:25])([O-])=O.[Cs+].[Cs+].CN([CH:31]=[O:32])C>>[CH3:22][O:25][C:31](=[O:32])[C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:10][O:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:10]3[N:9]=[C:8]([CH:18]4[CH2:21][CH2:20][CH2:19]4)[N:4]4[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=34)[CH:12]=2)[CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: Nc1nccn2c(C3CCC3)nc(-c3cccc(O)c3)c12
Agent: [Cs+]
Product: COC(=O)c1cccc(COc2cccc(-c3nc(C4CCC4)n4ccnc(N)c34)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenol (2.87 g, 10.2 mmol) in DMF was charged with Cs2CO3 (4.98 g, 15.3 mmol) and stirred at rt for 30 min. A DMF solution of methyl (3-bromomethyl)benzoate (2.33 g, 10.2 mmol) was added to the reaction mixture. The reaction mixture was stirred overnight at rt under nitrogen. The crude product was placed under high vacuum to remove the residual DMF. The product was then purified using silica gel column chromatography (1% NH3 in MeOH:CH2Cl2). The product was recrystalized with CH2Cl2 and hexanes to yield the title compounds as a white solid; 1H NMR (CDCl3, 400 MHz) δ 2.00-2.07 (m, 1H), 2.11-2.22 (m, 1H), 2.45-2.52 (m, 2H), 2.58-2.68 (m, 2H), 3.76-3.85 (m, 1H), 3.93 (s, 3H), 5.18 (s, 2H), 7.01-7.04 (m, 2H), 7.10-7.11 (m, 1H), 7.24-7.29 (m, 2H), 7.38-7.49 (m, 2H), 7.65 (d, J=7.6 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 8.13 (s, 1H); MS (ES+): m/z 429.18 (100) [MH+].
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.[CH2:13]([O:15][S:16]([O:19]CC)(=[O:18])=[O:17])[CH3:14]>>[CH2:13]([O:15][S:16]([OH:19])(=[O:18])=[O:17])[CH3:14].[CH3:1][CH:2]1[N:6]([CH2:13][CH3:14])[C:5]2[CH:7]=[C:8]([Cl:12])[CH:9]=[C:10]([Cl:11])[C:4]=2[O:3]1
Reactant: Cc1nc2cc(Cl)cc(Cl)c2o1
Reactant: CCOS(=O)(=O)OCC
Product: CCN1c2cc(Cl)cc(Cl)c2OC1C
Product: CCOS(=O)(=O)O
Temperature: 150 °C

Procedure:
A mixture of 2.0 g of 2-methyl-5,7-dichloro-benzoxazole and 2.5 ml of diethyl-sulphate was heated at 150° C for 40 minutes. By cooling, a solid cake was obtained. It was then ground in a mortar by washing repeatedly with ethyl ether. The product was employed without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=O)=[CH:5][NH:4][N:3]=1.CO[CH:16](OC)[CH2:17][CH:18](OC)OC.C(O)(=[O:27])C>>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:7]1[C:6]([CH:5]=[O:27])=[C:2]2[N:1]=[CH:16][CH:17]=[CH:18][N:3]2[N:4]=1
Reactant: Nc1n[nH]cc1C(=O)c1ccco1
Reactant: COC(CC(OC)OC)OC
Reactant: CC(=O)O
Product: O=Cc1c(-c2ccco2)nn2cccnc12

Procedure:
A mixture of 7.08 g of (3-amino-1H-pyrazol-4-yl)-2-furanylmethanone (prepared as described in U.S. Pat. appliction Ser. No. 612,811, filed May 24, 1984), 8.20 g of malonaldehyde bis(dimethyl acetal) and 100 ml of glacial acetic acid was heated at reflux for 8 hours. The solvent was evaporated and the solid was worked up as described in Example 50 to give 4.92 g of 2-furanylpyrazolo[1,5-a]pyrimidin-3-yl-methanone, mp 222°-224° C.
Reaction SMILES: Cl[CH:2]([Cl:4])C.[C:5]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].[O:18]1CCCOO1>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4].O>[C:5]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:18][CH2:2][Cl:4])=[O:14])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(Cl)Cl
Reactant: C1COOOC1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)OCCl)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 10 ml of dichloroethane were added 1.1 g of zirconium tetrachloride and 1 g of 4-t-butylbenzoyl chloride, and the mixture was stirred at room temperature for 20 minutes. The mixture was cooled to 0° C., 0.19 g of trioxane was added, and the mixture was stirred at room temperature for 1 hour. Water was added slowly at 0° C., the resultant solution was extracted with chloroform three times, and the organic layers were combined, washed with an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated to obtain 0.65 g of chloromethyl 4-t-butylbenzoate.
Reaction SMILES: [C:1]1(=[O:21])[N:5]([CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7](O)=[O:8])[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12.C(N1C=CN=C1)([N:24]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.CN(C)C1C=CN=CC=1.O>[C:1]1(=[O:21])[N:5]([CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([NH2:24])=[O:8])[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)C(c1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: CN(C)c1ccncc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)C(c1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
To a stirred mixture of 2-phthalimido-2-phenylacetic acid (2.50 g, 8.89 mmoL) in tetrahydrofuran (50 mL) is added carbonyldiimidazole (1.50 g, 9.25 mmoL) and a few crystals of 4-dimethylaminopyridine. The reaction is then heated to 50° C. for 45 minutes. After the reaction mixture cools to room temperature, 1 mL of concentrated ammonium hydroxide is added via syringe. The reaction is stirred for 1 hour, then diluted with 50 mL of water and partially concentrated to remove the majority of the tetrahydrofuran. The resulting slurry is filtered and the solid washed with copious amounts of water. The solid is dried in vacuo (60° C., <1 mm) to afford 1.9 g (76%) of 2-phthalimido-2-phenylacetamide, which may be alternatively named as N-phthaloylphenylglycinamide, as an off-white powder: mp 218°-220° C.; 1H NMR (DMSO-d6) δ 9.00-7.75 (m, 4 H, Ar), 7.61 (br s, 1 H, CONH2), 7.55-7.20 (m, 6 H, Ar, CONH2), 5.82 (s, 1 H, CHCO2); 13C NMR (DMSO-d6) δ 168.2, 167.1, 135.6, 134.5, 131.4, 129.4, 127.9, 127.7, 123.1, 56.3. Anal (C16H12N2O3), C, H, N.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:18][N:17]([CH2:26][CH2:27][F:28])[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CCOC(C)=O.CCO.[Pd]>[F:28][CH2:27][CH2:26][N:17]1[CH:18]=[C:19]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[N:16]1
Reactant: FCCn1cc(-c2ccncc2)c(-c2ccc(OCc3ccccc3)cc2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Oc1ccc(-c2nn(CCF)cc2-c2ccncc2)cc1
Reaction time: 18 h
Yield: 91.6 %

Procedure:
Pd/C (1 g) was added to a solution of Intermediate 3B, 4-(3-(4-(benzyloxy)phenyl)-1-(2-fluoroethyl)-1H-pyrazol-4-yl)pyridine (2.1 g) in EtOAc/EtOH (30 mL+30 mL). The mixture was stirred in autoclave at 2.5 atm H2 for 18 h. Pd/C was filtered off and the filtrate was concentrated under reduced pressure to yield the crude product. Purification by flash column chromatography afforded the pure product, 4-(1-(2-fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenol (1.46 g, 92%). 1H NMR (300 MHz, methanol-d4) δ 8.37 (dd, J=4.6, 1.6, 2H), 8.08 (s, 1H), 7.31 (dd, J=4.6, 1.7, 2H), 7.27-7.22 (m, 2H), 6.83-6.78 (m, 2H), 4.81 (dt, J=47.1, 4.7, 2H), 4.49 (dt, J=26.6, 4.7, 2H). MS (DCI—NH3) m/z=284 (M+H)+. (Note: Alternative preparation experimental details published in Journal of Medicinal Chemistry 2011, 54, 5820-5835, Compound 8b)
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([OH:11])([CH3:10])[CH3:9].C([Li])CCC.Cl[CH2:18][C:19]([OH:21])=[O:20].O>C1(C)C=CC=CC=1>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([O:11][CH2:18][C:19]([OH:21])=[O:20])([CH3:9])[CH3:10]
Reactant: CC(C)(O)C1CC2C=CC1C2
Reactant: O=C(O)CCl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(OCC(=O)O)C1CC2C=CC1C2
Temperature: 25 °C
Yield: 31.4 %

Procedure:
2-(5-norbornen-2-yl)-2-propanol (15.20 g, 0.10 mole) (JSR Corp., Japan) and toluene (100 ml) were added to a three-necked 500 ml round bottomed flask equipped with a magnetic stirrer, an addition funnel, and a condenser with a nitrogen inlet. The addition funnel was charged with n-butyl lithium (1.6M in hexane, 62.50 ml, 0.10 mole). The n-butyl lithium was added drop wise while stirring at room temperature. An exothermic reaction occurred. Afterwards, chloroacetic acid (4.75 g, 0.05 mole) in toluene (100 ml) was added drop wise. The contents were heated to reflux for about 20 hours. After cooling to room temperature, water (200 ml) was added cautiously and stirred. The water phase was collected, washed with ether (100 ml) and neutralized with 2 molar hydrochloric acid solution. The cloudy solution was extracted twice with ether (100 ml) and the combined ether solutions was washed with brine (100 ml) and dried over anhydrous magnesium sulfate. The solvent was removed and the residue was recrystallized from a small amount of hexane to give 3.3 g of white crystalline material (Melting Point: 48.5-49.50° C).
Reaction SMILES: C(N(CC)CC)C.[F:8][CH2:9][CH:10](O)[CH2:11][N:12]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH:14](O)[CH2:15][F:16].CS(Cl)(=O)=O.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.C(O)C>[CH2:31]([N:38]1[CH:10]([CH2:9][F:8])[CH2:11][N:12]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH:14]1[CH2:15][F:16])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCc1ccccc1
Reactant: OC(CF)CN(Cc1ccccc1)CC(O)CF
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: FCC1CN(Cc2ccccc2)CC(CF)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
28.89 g (0.286 mole) of triethylamine were added to a solution of 33.67 g (0.13 mole) of N,N-bis(3-fluoro-2-hydroxypropyl)benzylamine [prepared as described in step (a) above] in 300 ml of tetrahydrofuran. 32.76 g (0.286 mole) of methanesulfonyl chloride were then added dropwise to the mixture, whilst ice-cooling. After the mixture had been stirred at room temperature for 6 hours, 39.40 g (0.39 mole) of triethylamine, 20.87 g (0.195 mole) of benzylamine and 300 ml of ethanol were added to it, and it was then heated under reflux for 3 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and 300 ml of water containing 30 g of sodium hydroxide were added to the residue. The aqueous mixture thus obtained was extracted with ethyl acetate and the organic extracts were washed with water, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel using a 20:1 by volume mixture of toluene and ethyl acetate as the eluent, to afford 1,4-dibenzyl-2,6-bis(fluoromethyl)piperazine, including 6.29 g of isomer A and 6.60 g of isomer B, as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)#[CH:2].I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17]>>[C:6]1([CH3:9])[CH:7]=[CH:8][C:3]([C:1]2[O:17][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH:2]=2)=[CH:4][CH:5]=1
Reactant: Oc1ccccc1I
Reactant: C#Cc1ccc(C)cc1
Product: Cc1ccc(-c2cc3ccccc3o2)cc1

Procedure:
The general procedure was used to convert 4-ethynyl-toluene and 2-iodophenol to the title product. Purification by flash chromatography (10% CH2Cl2 in hexanes as the eluent) gave the analytically pure product as a white solid (268 mg, 64% yield). 1H NMR (300 MHz, CDCl3) δ 7.74 (d, J=8.29, 2H), 7.56-7.48 (m, 2H), 7.28-7.17 (m, 4H), 6.93 (s, 1H), 2.37 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 156.16, 154.75, 138.56, 132.85, 129.47, 127.73, 124.86, 123.97, 122.84, 120.72, 111.07, 100.54, 21.36 Anal. Calcd. for C15H12O: C, 86.51; H, 5.81. Found C, 86.34; H, 5.98. m.p.: 124-125° C. (lit., 3126-128° C.).